tbuckley/cabot-search huggingface dataset:
Metabolic biomarkers significantly enhance the prediction of HBV-related ACLF occurrence and outcomes
Authors: Yan Zhang, Wenting Tan, Xianbo Wang, Xin Zheng, Yan Huang, Beiling Li, Zhongji Meng, Yanhang Gao, Zhiping Qian, Feng Liu, Xiaobo Lu, Yu Shi, Jia Shang, Huadong Yan, Yubao Zheng, Weituo Zhang, Wenyi Gu, Liang Qiao, Guohong Deng, Yi Zhou, Yixin Hou, Qun Zhang, Shue Xiong, Jing Liu, Lihua Duan, Ruochan Chen, Jinjun Chen, Xiuhua Jiang, Sen Luo, Yuanyuan Chen, Chang Jiang, Jinming Zhao, Liujuan Ji, Xue Mei, Jing Li, Tao Li, Rongjiong Zheng, Xinyi Zhou, Haotang Ren, Xiaoliang Cheng, Lining Guo, Hai Li
Journal: Journal of Hepatology (2023)
Disease activity drives transcriptomic heterogeneity in early untreated rheumatoid synovitis
Authors: Clément Triaille, Gaëlle Tilman, Tatiana Sokolova, Axelle Loriot, Joelle Marchandise, Stéphanie De Montjoye, Adrien Nzeusseu-Toukap, Laurent Méric de Bellefon, Caroline Bouzin, Christine Galant, Patrick Durez, Bernard R Lauwerys, Nisha Limaye
Journal: Annals of the Rheumatic Diseases (2023)

Transcriptomic profiling of synovial tissue from patients with early, untreated rheumatoid arthritis (RA) was used to explore the ability of unbiased, data-driven approaches to define clinically relevant subgroups.RNASeq was performed on 74 samples, with disease activity data collected at inclusion. Principal components analysis (PCA) and unsupervised clustering were used to define patient clusters based on expression of the most variable genes, followed by pathway analysis and inference of relative abundance of immune cell subsets. Histological assessment and multiplex immunofluorescence (for CD45, CD68, CD206) were performed on paraffin sections.PCA on expression of the (n=894) most variable genes across this series did not divide samples into distinct groups, instead yielding a continuum correlated with baseline disease activity. Two patient clusters (PtC1, n=52; PtC2, n=22) were defined based on expression of these genes. PtC1, with significantly higher disease activity and probability of response to methotrexate therapy, showed upregulation of immune system genes; PtC2 showed upregulation of lipid metabolism genes, described to characterise tissue resident or M2-like macrophages. In keeping with these data, M2-like:M1-like macrophage ratios were inversely correlated with disease activity scores and were associated with lower synovial immune infiltration and the presence of thinner, M2-like macrophage-rich synovial lining layers.In this large series of early, untreated RA, we show that the synovial transcriptome closely mirrors clinical disease activity and correlates with synovial inflammation. Intriguingly, lower inflammation and disease activity are associated with higher ratios of M2:M1 macrophages, particularly striking in the synovial lining layer. This may point to a protective role for tissue resident macrophages in RA.
Clinical targeting of the cerebral oxygen cascade to improve brain oxygenation in patients with hypoxic–ischaemic brain injury after cardiac arrest
Authors: Ryan L. Hoiland, Chiara Robba, David K. Menon, Giuseppe Citerio, Claudio Sandroni, Mypinder S. Sekhon
Journal: Intensive Care Medicine (2023)

The cerebral oxygen cascade includes three key stages: (a) convective oxygen delivery representing the bulk flow of oxygen to the cerebral vascular bed; (b) diffusion of oxygen from the blood into brain tissue; and (c) cellular utilisation of oxygen for aerobic metabolism. All three stages may become dysfunctional after resuscitation from cardiac arrest and contribute to hypoxic–ischaemic brain injury (HIBI). Improving convective cerebral oxygen delivery by optimising cerebral blood flow has been widely investigated as a strategy to mitigate HIBI. However, clinical trials aimed at optimising convective oxygen delivery have yielded neutral results. Advances in the understanding of HIBI pathophysiology suggest that impairments in the stages of the oxygen cascade pertaining to oxygen diffusion and cellular utilisation of oxygen should also be considered in identifying therapeutic strategies for the clinical management of HIBI patients. Culprit mechanisms for these impairments may include a widening of the diffusion barrier due to peri-vascular oedema and mitochondrial dysfunction. An integrated approach encompassing both intra-parenchymal and non-invasive neuromonitoring techniques may aid in detecting pathophysiologic changes in the oxygen cascade and enable patient-specific management aimed at reducing the severity of HIBI.
Growth rates and histopathological outcomes of small (6–9 mm) colorectal polyps based on CT colonography surveillance and endoscopic removal
Authors: B Dustin Pooler, David H Kim, Kristina A Matkowskyj, Michael A Newton, Richard B Halberg, William M Grady, Cesare Hassan, Perry J Pickhardt
Journal: Gut (2023)

Background and aims The natural history of small polyps is not well established and rests on limited evidence from barium enema studies decades ago. Patients with one or two small polyps (6–9 mm) at screening CT colonography (CTC) are offered CTC surveillance at 3 years but may elect immediate colonoscopy. This practice allows direct observation of the growth of subcentimetre polyps, with histopathological correlation in patients undergoing subsequent polypectomy. Design Of 11 165 asymptomatic patients screened by CTC over a period of 16.4 years, 1067 had one or two 6–9 mm polyps detected (with no polyps ≥10 mm). Of these, 314 (mean age, 57.4 years; M:F, 141:173; 375 total polyps) elected immediate colonoscopic polypectomy, and 382 (mean age 57.0 years; M:F, 217:165; 481 total polyps) elected CTC surveillance over a mean of 4.7 years. Volumetric polyp growth was analysed, with histopathological correlation for resected polyps. Polyp growth and regression were defined as volume change of ±20% per year, with rapid growth defined as +100% per year (annual volume doubling). Regression analysis was performed to evaluate predictors of advanced histology, defined as the presence of cancer, high-grade dysplasia (HGD) or villous components. Results Of the 314 patients who underwent immediate polypectomy, 67.8% (213/314) harboured adenomas, 2.2% (7/314) with advanced histology; no polyps contained cancer or HGD. Of 382 patients who underwent CTC surveillance, 24.9% (95/382) had polyps that grew, while 62.0% (237/382) remained stable and 13.1% (50/382) regressed in size. Of the 58.6% (224/382) CTC surveillance patients who ultimately underwent colonoscopic resection, 87.1% (195/224) harboured adenomas, 12.9% (29/224) with advanced histology. Of CTC surveillance patients with growing polyps who underwent resection, 23.2% (19/82) harboured advanced histology vs 7.0% (10/142) with stable or regressing polyps (OR: 4.0; p&lt;0.001), with even greater risk of advanced histology in those with rapid growth (63.6%, 14/22, OR: 25.4; p&lt;0.001). Polyp growth, but not patient age/sex or polyp morphology/location were significant predictors of advanced histology. Conclusion Small 6–9 mm polyps present overall low risk to patients, with polyp growth strongly associated with higher risk lesions. Most patients (75%) with small 6–9 mm polyps will see polyp stability or regression, with advanced histology seen in only 7%. The minority of patients (25%) with small polyps that do grow have a 3-fold increased risk of advanced histology.
Targeting MS4A4A on tumour-associated macrophages restores CD8+ T-cell-mediated antitumour immunity
Authors: Yongsheng Li, Zhiyong Shen, Zhen Chai, Yizhi Zhan, Yaowei Zhang, Zhengyu Liu, Yuechen Liu, Zhenkang Li, Mingdao Lin, Zhanqiao Zhang, Wei Liu, Shenyuan Guan, Jinchao Zhang, Junying Qian, Yi Ding, Guoxin Li, Yuan Fang, Haijun Deng
Journal: Gut (2023)

Objective Checkpoint immunotherapy unleashes T-cell control of tumours but is suppressed by immunosuppressive myeloid cells. The transmembrane protein MS4A4A is selectively highly expressed in tumour-associated macrophages (TAMs). Here, we aimed to reveal the role of MS4A4A + TAMs in regulating the immune escape of tumour cells and to develop novel therapeutic strategies targeting TAMs to enhance the efficacy of immune checkpoint inhibitor (ICI) in colorectal cancer. Design The inhibitory effect of MS4A4A blockade alone or combined with ICI treatment on tumour growth was assessed using murine subcutaneous tumour or orthotopic transplanted models. The effect of MS4A4A blockade on the tumour immune microenvironment was assessed by flow cytometry and mass cytometry. RNA sequencing and western blot analysis were used to further explore the molecular mechanism by which MS4A4A promoted macrophages M2 polarisation. Results MS4A4A is selectively expressed by TAMs in different types of tumours, and was associated with adverse clinical outcome in patients with cancer. In vivo inhibition of MS4A4A and anti-MS4A4A monoclonal antibody treatment both curb tumour growth and improve the effect of ICI therapy. MS4A4A blockade treatment reshaped the tumour immune microenvironment, resulting in reducing the infiltration of M2-TAMs and exhausted T cells, and increasing the infiltration of effector CD8 + T cells. Anti-MS4A4A plus anti-programmed cell death protein 1 (PD-1) therapy remained effective in large, treatment-resistant tumours and could induce complete regression when further combined with radiotherapy. Mechanistically, MS4A4A promoted M2 polarisation of macrophages by activating PI3K/AKT pathway and JAK/STAT6 pathway. Conclusion Targeting MS4A4A could enhance the ICI efficacy and represent a new anticancer immunotherapy.
Metal‐Free Peroxidase‐Mimetic Nanocatalysts for Chemodynamic Vascular‐Disrupting Cancer Therapy
Authors: Zihao Sun, Chen Zhou, Yue Zhou, Shenge Su, Chunru Wang, Mingming Zhen
Journal: Advanced Healthcare Materials (2023)

Metal ion-facilitated chemodynamic therapy (CDT) is an emerging method for treating cancer. However, its potential is hindered by its low catalytic performance in weakly acidic tumor microenvironments (TMEs) and the severe toxicity of free metal ions. A new approach to tumor therapy, chemodynamic vascular disruption (CVD), is introduced using metal-free, peroxidase (POD)-mimetic multihydroxylated [70] fullerene (MHF) nanocatalysts. The research shows that MHF contains C···O active sites, as demonstrated by density functional theory (DFT) calculations, and converts H2 O2 into ∙OH across a pH range of 6.0-10.0. The generation of ∙OH and the dismantling of tumor blood vessels are observed in real-time using mouse dorsal skin-fold chamber (DSFC) models. Applying proteomics, it is discovered that the CVD mechanism involves the nanocatalytic MHF enhancing H2 O2 decomposition in the TME, producing ∙OH. This damages tumor vascular endothelial junction proteins, causing vascular leakage and subsequently cutting off the vascular supply to the tumor cells. This method deviates from the traditional CDT that targets tumor cells. Instead, the proficient MHF nanocatalysts aim to directly disrupt the tumor vasculature, enhancing anti-tumor efficiency without triggering harmful toxicity. The proposed CVD therapeutic strategy enhances the application of gentle carbon nanocatalysts in cancer therapy, offering new perspectives on nanocatalytic medicine.
Protection against Metabolic Associated Fatty Liver Disease by Protocatechuic Acid
Authors: Jijun Tan, Ruizhi Hu, Jiatai Gong, Chengkun Fang, Yanli Li, Ming Liu, Ziyu He, De-Xing Hou, Hongfu Zhang, Jianhua He, Shusong Wu
Journal: Gut Microbes (2023)

Gut microbiota-diet interaction has been identified as a key factor of metabolic associated fatty liver disease (MAFLD). Recent studies suggested that dietary polyphenols may protect against MAFLD by regulating gut microbiota; however, the underlying mechanisms remain elusive. We first investigated the effects of cyanidin 3-glucoside and its phenolic metabolites on high-fat diet induced MAFLD in C57BL/6J mice, and protocatechuic acid (PCA) showed a significant positive effect. Next, regulation of PCA on lipid metabolism and gut microbiota were explored by MAFLD mouse model and fecal microbiota transplantation (FMT) experiment. Dietary PCA reduced intraperitoneal and hepatic fat deposition with lower levels of transaminases (AST & ALT) and inflammatory cytokines (IL-1β, IL-2, IL-6, TNF-α & MCP-1), but higher HDL-c/LDL-c ratio. Characterization of gut microbiota indicated that PCA decreased the Firmicutes/Bacteroidetes ratio mainly by reducing the relative abundance of genus Enterococcus, which was positively correlated with the levels of LDL-c, AST, ALT and most of the up-regulated hepatic lipids by lipidomics analysis. FMT experiments showed that Enterococcus faecalis caused hepatic inflammation, fat deposition and insulin resistance with decreased expression of carnitine palmitoyltransferase-1 alpha (CPT1α), which can be reversed by PCA through inhibiting Enterococcus faecalis. Transcriptomics analysis suggested that Enterococcus faecalis caused a significant decrease in the expression of fibroblast growth factor 1 (Fgf1), and PCA recovered the expression of Fgf1 with insulin-like growth factor binding protein 2 (Igfbp2), insulin receptor substrate 1 (Irs1) and insulin receptor substrate 2 (Irs2). These results demonstrated that high proportion of gut Enterococcus faecalis accelerates MAFLD with decreased expression of CPT1α and Fgf1, which can be prevented by dietary supplementation of PCA.
Morphological and transcriptomic analyses of stem cell-derived cortical neurons reveal mechanisms underlying synaptic dysfunction in schizophrenia
Authors: Annie Kathuria, Kara Lopez-Lengowski, Bradley Watmuff, Rakesh Karmacharya
Journal: Genome Medicine (2023)

Abstract Background Postmortem studies in schizophrenia consistently show reduced dendritic spines in the cerebral cortex but the mechanistic underpinnings of these deficits remain unknown. Recent genome-wide association studies and exome sequencing investigations implicate synaptic genes and processes in the disease biology of schizophrenia. Methods We generated human cortical pyramidal neurons by differentiating iPSCs of seven schizophrenia patients and seven healthy subjects, quantified dendritic spines and synapses in different cortical neuron subtypes, and carried out transcriptomic studies to identify differentially regulated genes and aberrant cellular processes in schizophrenia. Results Cortical neurons expressing layer III marker CUX1, but not those expressing layer V marker CTIP2, showed significant reduction in dendritic spine density in schizophrenia, mirroring findings in postmortem studies. Transcriptomic experiments in iPSC-derived cortical neurons showed that differentially expressed genes in schizophrenia were enriched for genes implicated in schizophrenia in genome-wide association and exome sequencing studies. Moreover, most of the differentially expressed genes implicated in schizophrenia genetic studies had lower expression levels in schizophrenia cortical neurons. Network analysis of differentially expressed genes led to identification of NRXN3 as a hub gene, and follow-up experiments showed specific reduction of the NRXN3 204 isoform in schizophrenia neurons. Furthermore, overexpression of the NRXN3 204 isoform in schizophrenia neurons rescued the spine and synapse deficits in the cortical neurons while knockdown of NRXN3 204 in healthy neurons phenocopied spine and synapse deficits seen in schizophrenia cortical neurons. The antipsychotic clozapine increased expression of the NRXN3 204 isoform in schizophrenia cortical neurons and rescued the spine and synapse density deficits. Conclusions Taken together, our findings in iPSC-derived cortical neurons recapitulate cell type-specific findings in postmortem studies in schizophrenia and have led to the identification of a specific isoform of NRXN3 that modulates synaptic deficits in schizophrenia neurons.
ChatGPT for shaping the future of dentistry: the potential of multi-modal large language model
Authors: Hanyao Huang, Ou Zheng, Dongdong Wang, Jiayi Yin, Zijin Wang, Shengxuan Ding, Heng Yin, Chuan Xu, Renjie Yang, Qian Zheng, Bing Shi
Journal: International Journal of Oral Science (2023)

The ChatGPT, a lite and conversational variant of Generative Pretrained Transformer 4 (GPT-4) developed by OpenAI, is one of the milestone Large Language Models (LLMs) with billions of parameters. LLMs have stirred up much interest among researchers and practitioners in their impressive skills in natural language processing tasks, which profoundly impact various fields. This paper mainly discusses the future applications of LLMs in dentistry. We introduce two primary LLM deployment methods in dentistry, including automated dental diagnosis and cross-modal dental diagnosis, and examine their potential applications. Especially, equipped with a cross-modal encoder, a single LLM can manage multi-source data and conduct advanced natural language reasoning to perform complex clinical operations. We also present cases to demonstrate the potential of a fully automatic Multi-Modal LLM AI system for dentistry clinical application. While LLMs offer significant potential benefits, the challenges, such as data privacy, data quality, and model bias, need further study. Overall, LLMs have the potential to revolutionize dental diagnosis and treatment, which indicates a promising avenue for clinical application and research in dentistry.
Efficacy and tolerability of oral upadacitinib monotherapy in patients with recalcitrant vitiligo
Authors: Xinhong Su, Renwei Luo, Shifan Ruan, Qingmei Zhong, Zheyu Zhuang, Zhixun Xiao, Peng Zhang, Bo Cheng, Ting Gong, Chao Ji
Journal: Journal of the American Academy of Dermatology (2023)
Survival expectation after thrombosis and overt-myelofibrosis in essential thrombocythemia and prefibrotic myelofibrosis: a multistate model approach
Authors: Alessandra Carobbio, Alessandro Maria Vannucchi, Elisa Rumi, Valerio De Stefano, Alessandro Rambaldi, Giuseppe Carli, Maria Luigia Randi, Heinz Gisslinger, Francesco Passamonti, Juergen Thiele, Naseema Gangat, Ayalew Tefferi, Tiziano Barbui
Journal: Blood Cancer Journal (2023)
Novel ADCs and combination therapy in urothelial carcinoma: latest updates from the 2023 ASCO-GU Cancers Symposium
Authors: Jiazheng Yu, Siyu Wu, Rong Li, Yuanhong Jiang, Jianyi Zheng, Zeyu Li, Mingyang Li, Kerong Xin, Xiaojiao Guan, Shijie Li, Xiaonan Chen
Journal: Journal of Hematology & Oncology (2023)

Antibody-drug conjugates (ADCs) combine the cytotoxicity of small-molecule drugs with antibody targeting. Due to their precise and powerful effect, they have become a new hotspot and an important trend in the research and development of anti-tumor antibody drugs. Every year, exciting new developments and innovations in the treatment of urological tumors are introduced at the American Society of Clinical Oncology-Genitourinary (ASCO-GU) Cancers Symposium. In this article, we summarize some of the most impressive advances in new clinical trials and clinical data on ADCs in the 2023 ASCO-GU Cancers Symposium for the treatment of urothelial carcinoma.
BCMA-targeted CAR-T cell therapies in relapsed and/or refractory multiple myeloma: latest updates from 2023 ASCO Annual Meeting
Authors: James F. Wu, Binod Dhakal
Journal: Journal of Hematology & Oncology (2023)

Abstract Treatment of relapsed and/or refractory multiple myeloma (RRMM) utilizing the novel therapeutic target of the B-cell maturation antigen (BCMA) has demonstrated incredible results, leading to regulatory approval of BCMA-targeted chimeric antigen receptor (CAR)-T cell therapies in RRMM. With now two approved BCMA-targeted CAR-T cell therapies, investigators globally are working to build off and improve upon BCMA-targeted therapies. We discuss long-term data from the pivotal study that led to CAR-T approval, a phase 3 trial supporting their use in earlier lines, and novel manufacturing platforms to decrease vein-to-vein time. We highlight five key abstracts from the 2023 ASCO Annual Meeting that showcase these exciting updates in BCMA-directed CAR-T cell therapies in RRMM.
How to reduce medications for people with multiple long term conditions
Authors: Helen Saul, Samantha Cassidy, Brendan Deeney, Candace Imison, Joanne Reeve
Journal: BMJ (2023)

The studyReeve J, Maden M, Hill R, et al. Deprescribing medicines in older people living with multimorbidity and polypharmacy: the TAILOR evidence synthesis. Health Technol Assess 2022;26:1-148.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/how-to-safely-deprescribe-medications-for-people-with-multiple-long-term-conditions/.
The JAK1/2 inhibitor ruxolitinib in patients with COVID-19 triggered hyperinflammation: the RuxCoFlam trial
Authors: J. Hammersen, S. Birndt, K. Döhner, P. Reuken, A. Stallmach, P. Sauerbrey, F. La Rosée, M. Pfirrmann, C. Fabisch, M. Weiss, K. Träger, H. Bremer, S. Russo, G. Illerhaus, D. Drömann, S. Schneider, P. La Rosée, A. Hochhaus
Journal: Leukemia (2023)

Abstract Dysregulated hyperinflammatory response is key in the pathogenesis in patients with severe COVID-19 leading to acute respiratory distress syndrome and multiorgan failure. Whilst immunosuppression has been proven to be effective, potential biological targets and optimal timing of treatment are still conflicting. We sought to evaluate efficacy and safety of the Janus Kinase 1/2 inhibitor ruxolitinib, employing the previously developed COVID-19 Inflammation Score (CIS) in a prospective multicenter open label phase II trial (NCT04338958). Primary objective was reversal of hyperinflammation (CIS reduction of ≥25% at day 7 in ≥20% of patients). In 184 patients with a CIS of ≥10 (median 12) ruxolitinib was commenced at an initial dose of 10 mg twice daily and applied over a median of 14 days (range, 2–31). On day 7, median CIS declined to 6 (range, 1–13); 71% of patients (CI 64–77%) achieved a ≥25% CIS reduction accompanied by a reduction of markers of inflammation. Median cumulative dose was 272.5 mg/d. Treatment was well tolerated without any grade 3–5 adverse events related to ruxolitinib. Forty-four patients (23.9%) died, all without reported association to study drug. In conclusion, ruxolitinib proved to be safe and effective in a cohort of COVID-19 patients with defined hyperinflammation.
Publisher Correction: Neoadjuvant adebrelimab in locally advanced resectable esophageal squamous cell carcinoma: a phase 1b trial
Authors: Jun Yin, Jingnan Yuan, Yunjin Li, Yong Fang, Ruoxi Wang, Heng Jiao, Han Tang, Shaoyuan Zhang, Siyun Lin, Feng Su, Jianmin Gu, Tian Jiang, Dong Lin, Zhiliang Huang, Chaoxiang Du, Kui Wu, Lijie Tan, Qing Zhou
Journal: Nature Medicine (2023)
Pulmonary delivery of mucus-traversing PF127-modified silk fibroin nanoparticles loading with quercetin for lung cancer therapy
Authors: Yu Tang, Lanfang Zhang, Rui Sun, Baiyi Luo, Yu Zhou, Yan Zhang, Yuqi Liang, Bo Xiao, Chenhui Wang
Journal: Asian Journal of Pharmaceutical Sciences (2023)

The mucosal barrier remains a major barrier in the pulmonary drug delivery system, as mucociliary clearance in the airway accelerates the removal of inhaled nanoparticles (NPs). Herein, we designed and developed the inhalable Pluronic F127-modified silk fibroin NPs loading with quercetin (marked as QR-SF (PF127) NPs), aiming to solve the airway mucus barrier and improve the cancer therapeutic effect of QR. The PF127 coating on the SF NPs could attenuate the interaction between NPs and mucin proteins, thus facilitating the diffusion of SF(PF127) NPs in the mucus layer. The QR-SF (PF127) NPs had particle sizes of approximately 200 nm with negatively charged surfaces and showed constant drug release properties. Fluorescence recovery after photobleaching (FRAP) assay and transepithelial transport test showed that QR-SF (PF127) NPs exhibited superior mucus-penetrating ability in artificial mucus and monolayer Calu-3 cell model. Notably, a large amount of QR-SF (PF127) NPs distributed uniformly in the mice airway section, indicating the good retention of NPs in the respiratory tract. The mice melanoma lung metastasis model was established, and the therapeutic effect of QR-SF (PF127) NPs was significantly improved in vivo. PF127-modified SF NPs may be a promising strategy to attenuate the interaction with mucin proteins and enhance mucus penetration efficiency in the pulmonary drug delivery system.